Anal cancer in Sweden 2015-2019. Implementation of guidelines, structural changes, national registry and early results.

BACKGROUND: Squamous cell cancer of the anus is an uncommon malignancy, usually caused by human papilloma virus (HPV). Chemoradiotherapy (CRT) is the recommended treatment in localized disease with cure rates of 60-80%. Local failures should be considered for salvage surgery. With the purpose of improving and equalizing the anal cancer care in Sweden, a number of actions were taken between 2015 and 2017. The aim of this study was to describe the implementation of guidelines and organizational changes and to present early results from the first 5 years of the Swedish anal cancer registry (SACR). METHODS: The following were implemented: (1) the first national care program with treatment guidelines, (2) standardized care process, (3) centralization of CRT to four centers and salvage surgery to two centers, (4) weekly national multidisciplinary team meetings where all new cases are discussed, (5) the Swedish anal cancer registry (SACR) was started in 2015. RESULTS: The SACR included 912 patients with a diagnosis of anal cancer from 2015 to 2019, reaching a national coverage of 95%. We could show that guidelines issued in 2017 regarding staging procedures and radiotherapy dose modifications were rapidly implemented. At baseline 52% of patients had lymph node metastases and 9% had distant metastases. Out of all patients in the SACR 89% were treated with curative intent, most of them with CRT, after which 92% achieved a local complete remission and the estimated overall 3-year survival was 85%. CONCLUSIONS: This is the first report from the SACR, demonstrating rapid nation-wide implementation of guidelines and apparently good treatment outcome in patients with anal cancer in Sweden. The SACR will hopefully be a valuable source for future research.

Evaluation of the stage classification of anal cancer by the TNM 8th version versus the TNM 7th version.

Background: The UICC TNM 7th edition introduced stage groups for anal cancer which in 2019 has not yet come into general use. The new TNM 8th edition from 2016 defines 7 sub-stages. Background data for these changes are lacking. We aimed to investigate whether the new classification for anal cancer reliably predict the prognosis in the different stages.Patients and methods: The Nordic Anal Cancer Group (NOAC) conducted a large retrospective study of all anal cancers in Norway, Sweden and most of Denmark in 2000-2007. From the Nordic cohort 1151 anal cancer patients with follow-up data were classified by the TNM 4th edition which has identical T, N and M definitions as the TNM 7th edition, and therefore also can be classified by the TNM 7th stage groups. We used the Nordic cohort to translate the T, N and M stages into the TNM 8th stages and sub-stages. Overall survival for each stage was assessed.Results: Although the summary stage groups for TNM 8th edition discriminates patients with different prognosis reasonably well, the analyses of the seven sub-stages show overlapping overall survival: HR for stage IIA 1.30 (95%CI 0.80-2.12) is not significantly different from stage I (p = .30) and HR for stage IIB 2.35 (95%CI 1.40-3.95) and IIIA 2.48 (95%CI 1.43-4.31) are also similar as were HRs for stage IIIB 3.41 (95%CI 1.99-5.85) and IIIC 3.22 (95%CI 1.99-5.20). Similar overlapping was shown for local recurrence and distant spread.Conclusion: The results for the sub-stages calls for a revision of the staging system. We propose a modification of the TNM 8th edition for staging of anal cancer into four stages based on the T, N and M definitions of the TNM 8th classification.

Patterns of recurrence in anal cancer: a detailed analysis.

BACKGROUND: Anal cancer is a rare disease, which might be the reason for the "one size fits all" approach still used for radiotherapy target contouring. To refine and individualize future guidelines, detailed and contemporary pattern of recurrence studies are needed. METHODS: Consecutive anal cancer patients, all treated with curative intent intensity-modulated radiotherapy (IMRT), were retrospectively studied (n = 170). Data was extracted from medical records and radiological images. Radiotherapy planning CT's and treatment plans were reviewed, and recurrences were mapped and categorized according to radiation dose. RESULTS: The mean dose to the primary tumor was 59.0 Gy. With a median follow-up of 50 months (range 14-117 months), 5-year anal cancer specific survival was 86.1%. Only 1 of 20 local recurrences was located outside the high dose (CTVT) volume. More patients experienced a distant recurrence (n = 34; 20.0%) than a locoregional recurrence (n = 24; 14.1%). Seven patients (4.2%) had a common iliac and/or para-aortic (CI/PA) recurrence. External iliac lymph node involvement (P = 0.04), and metastases in ≥3 inguinal or pelvic lymph node regions (P = 0.02) were associated with a 15-18% risk of CI/PA recurrence. Following chemoradiotherapy, 6 patients with recurrent or primary metastatic CI/PA lymph nodes were free of recurrence at last follow-up. The overall rate of ano-inguinal lymphatic drainage (AILD) recurrence was 2 of 170 (1.2%), and among patients with inguinal metastases at initial diagnosis it was 2 of 65 (3.1%). CONCLUSIONS: We conclude that other measures than increased margins around the primary tumor are needed to improve local control. Furthermore, metastatic CI/PA lymph nodes, either at initial diagnosis or in the recurrent setting, should be considered potentially curable. Patients with certain patterns of metastatic pelvic lymph nodes might be at an increased risk of harboring tumor cells also in the CI/PA lymph nodes.

Determinants for local tumour control probability after radiotherapy of anal cancer.

BACKGROUND AND PURPOSE: Anal squamous cell carcinoma is primarily treated with radiotherapy (RT), but the optimal RT dose for anal tumours of different sizes is not known. The purpose of this study was to identify determinants for local tumour control probability (LTCP). MATERIAL AND METHODS: From a large Nordic database 901 patients who received RT for anal cancer between 2000 and 2007 were selected. LTCP was analysed in a series of uni- and multivariable regression analyses. RESULTS: Higher RT dose, female gender and addition of chemotherapy were associated with higher LTCP whereas increasing tumour size, tumour invasiveness (stage T4) and lymph node metastases (N+) were associated with lower LTCP. Male patients needed approximately 10 Gy higher RT dose than female patients for similar LTCP. The addition of chemotherapy corresponded to 5-10 Gy RT dose. CONCLUSIONS: Our results basically support current guidelines recommending: (1) lower RT dose in small tumours (<4 cm), (2) higher RT dose larger tumours and in stages T4 and /or N+, (3) Chemo should be used in combination with RT. These results will hopefully constitute the basis for future trials, aiming at individualized RT dosing in patients with anal cancer.

Primary surgery with or without postoperative radiotherapy in early stage squamous cell carcinoma in the anal canal and anal margin.

BACKGROUND: Standard treatment of localized squamous cell carcinoma of the anus (SCCA) is radiotherapy (RT) combined with chemotherapy, that is, chemoradiation (CRT). Primary surgery has a limited role, but is a recommended treatment for small well differentiated SCCA localized in the anal margin, with re-excision or postoperative RT/CRT in case of involved surgical margins. The evidence supporting these strategies is limited. AIM: To study the recurrence patterns and survival outcomes in patients treated with surgery alone compared with surgery followed by postoperative RT/CRT. MATERIAL AND METHODS: From a large Nordic database we identified 93 patients with stage TxT1-2N0M0 SCCA treated with surgery alone (n = 59) or surgery followed by RT/CRT (n = 34). Surgery consisted of local excision in 86 patients and abdominoperineal resection in seven patients, all of them in the surgery alone group. In 38 (41%) of the patients, the tumor was localized merely in the anal margin and in all remaining cases the anal canal was involved. Median RT dose to the tumor bed was 54 (range 46-66) Gy. Adjuvant RT to lymph nodes was given in 75% of the patients. Half of the patients received concomitant chemotherapy, usually 5-fluorouracil and mitomycin C. RESULTS: The locoregional recurrence (LRR) rate was significantly higher after surgery alone compared to surgery followed by adjuvant RT/CRT (36% vs. 9%, p = .006). The 3-year recurrence free survival (RFS) and overall survival (OS) were significantly better in patients who received postoperative RT/CRT than in patients who did not (3-year RFS 84.2% vs. 52.7%, p < .001 and 3-year OS 87.2% vs. 70%, p = .026). CONCLUSIONS: Surgery alone of SCCA was associated with a high LRR rate and poor survival. The addition of postoperative RT/CRT lead to significantly improved locoregional control and survival.

Phase I study of cetuximab in combination with 5-fluorouracil, mitomycin C and radiotherapy in patients with locally advanced anal cancer.

BACKGROUND: 5-fluorouracil (5FU) and mitomycin C (MMC)-based chemoradiotherapy (CRT) is standard treatment for anal squamous cell carcinoma. In this phase I study cetuximab was added and the primary aim was to determine the maximum tolerated dose (MTD) of 5FU and MMC in this combination. METHODS AND MATERIALS: Patients with locally advanced anal cancer, T2 (≥4 cm)-4N0-3M0, received weekly standard doses of cetuximab starting 1 week before CRT. Intensity modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) with simultaneous integrated boost (SIB) was given to 57.5/54.0/48.6 Gy in 27 fractions to primary tumour/lymph node metastases/adjuvant lymph node regions. 5FU/MMC was given concomitantly on RT weeks 1 and 5 according to a predefined dose escalation schedule. RESULTS: Thirteen patients were enrolled. Two patients discontinued cetuximab due to hypersensitivity reaction. The median age was 65 years (range 46-70), nine were females, and 85% had stage IIIB disease. Dose-limiting toxicity events (diarrheoa, febrile neutropenia and thrombocytopenia) occurred in 3 of 11 patients. The most common grade 3-4 side-effects were radiation dermatitis (63%), haematologic toxicity (54%), and diarrheoa (36%). No treatment-related deaths occurred. Three months following completion of treatment, ten patients (91%) had a local complete remission (CR), but two patients had developed liver metastases, yielding a total CR rate of 73%. CONCLUSION: The MTDs were determined as 5FU 800 mg/m(2) on RT days 1-4 and 29-32 and MMC 8 mg/m(2) on days 1 and 29 when combined with IMRT/VMAT with SIB and cetuximab in locally advanced anal cancer.

Anal carcinoma - Survival and recurrence in a large cohort of patients treated according to Nordic guidelines.

OBJECTIVE: To evaluate treatment outcome in a large population-based cohort of patients with anal cancer treated according to Nordic guidelines. MATERIAL: Clinical data were collected on 1266 patients with anal squamous cell carcinoma diagnosed from 2000 to 2007 in Sweden, Norway and Denmark. 886 of the patients received radiotherapy 54-64Gy with or without chemotherapy (5-fluorouracil plus cisplatin or mitomycin) according to different protocols, stratified by tumor stage. RESULTS: High age, male gender, large primary tumor, lymph node metastases, distant metastases, poor performance status, and non-inclusion into a protocol were all independent factors associated with worse outcome. Among patients treated according to any of the protocols, the 3-year recurrence-free survival ranged from 63% to 76%, with locoregional recurrences in 17% and distant metastases in 11% of patients. The highest rate of inguinal recurrence (11%) was seen in patients with small primary tumors, treated without inguinal irradiation. CONCLUSIONS: Good treatment efficacy was obtained with Nordic, widely implemented, guidelines for treatment of anal cancer. Inguinal prophylactic irradiation should be recommended also for small primary tumors.